Germicidal process and detergent compositions

ABSTRACT

The use of N-Acyl-N&#39;&#39;-(halogenated aryl) ureas as antibacterial agents and germicidal detergent compositions containing such ureas are disclosed.

United States Patent [1 1 Taber et al.

[4 1 Feb. 19, 1974 1 GERMICIDAL PROCESS AND DETERGENT COMPOSITIONS [75]Inventors: David Taber, Evanston; Moneeb Zakaria, Chicago, both of 111.

[73] Assignee: Armour-Dial, Inc., Chicago, Ill.

[22] Filed: Jan. 24, 1972 [21] Appl. No.: 220,474

Related US. Application Data [62] Division of Ser. No. 868,937, Oct. 23,1969, Pat. No. 3,686,418, which is a division of Ser. No. 683,585, May15, 1967, abandoned.

[52] US. Cl..... 252/107, 252/106 [51] Int. Cl. Clld 3/48, Clld 9/50[58] Field ofSearch 252/106, 107; 424/322;

Primary Examiner-Leon D. Rosdol Assistant Examiner-P. E. WillisAttorney, Agent, or Firm--Frank T. Barber; Richard G. Harrer [5 7ABSTRACT The use of N-Acyl-N'-(halogenated aryl) ureas as antibacterialagents and germicidal detergent compositions containing such ureas aredisclosed.

8 Claims, N0 Drawings GERMICIDAL PROCESS AND DETERGENT COMPOSITIONS Thisis a division of our Pat. application Ser. No. 868,937 filed Oct. 23,1969, now Pat. No. 3,686,418 which in turn is adivision of Pat.application Ser. No. 638,585 filed May 15, 1967 and now abandoned.

This invention relates to new antibacterial agents and more particularlyto new germicidal detergent compositions.

The popularity of detergent compositions, for both laundry and toiletuse, containing new germicidal agents has increased tremendously overthe past few years. It is estimated that more than 20 percent of thetoilet bar soap sales are now of products containing a germicidal agent;and this percentage is steadily increasing. Heretofore many compoundshave been investigated as possible detergent germicides. While numeroussubstances indicate a degree of antibacterial activity, few produce thedesired results necessary for use as effective detergent germicides. Inmany cases the germicide is either incompatible with the detergent orelse germicidal activity is abated when the germicide is incorporatedinto the detergent. Further, certain detergent products, such as toiletsoap, have the added requirement that the germicide used must not beharmful to the human skin. Thus, it is desirable that a considerablevariety of germicides be made available, from which a selection may bemade for use in various detergent media.

One aspect of the present invention lies in the discovery that certainacyl ureas have definite antibacterial properties and that theseproperties are maintained in the presence of an alkaline agent such assoap or other detergent compositions. These compounds are, to the bestof our knowledge, not harmful to human skin.

Therefore, it is an object of this invention to provide newantibacterial agents which are compatible with detergent compositionsand which maintain this activity even when incorporated into detergentcompositions. Other objects and advantages, and a further understandingof this invention, will appear in the ensuing description and examples.

In one specific embodiment, our invention may be exemplified by anantiseptic detergent composition comprising a detergent and agermicidally effective amount of an N-acyl-N'-(halogenated aryl) ureacompound of the structure:

wherein R is a radical selected from the group consisting of aliphaticradicals containing from 2 to 13 carbon atoms and halogenated phenylradicals, X is halogen such as chlorine, bromine, fluorine,trichloromethyl, trifluoromethyl and the like, and n is an integer from1 to 5. This means that n may be 1 or 2, or 3, or 4, or 5.

N-acyl ureas of the above structure may be prepared generally byreacting either aliphatic amides (RCONH or halogenated benzamides (x -ArCOHN with a halogenated aryl isocyanate, such as 3,4-dichlorophenylisocyanate, in an inert solvent under anhydrous conditions and at refluxtemperatures. The above reaction may be illustrated by the foliscyanatuea ant H C1 wherein R is as defined hereinabove. The aryl radicalof the halogenated aryl isocyanate can contain other substitutions inaddition to the halogen, such as nitro and additional phenylsubstitutions. Further, the halogen substitutions on our acyl ureas maybe varied. Suitable halogenated radicals include chlorobenzyls,bromobenzyls, fluorobenzyls, chloromethylphenyls, dichloromethylphenyls,trichloromethylphenyls, trifluoromethylphenyls, chloronapthyls,bromonapthyls, fluoronapthyls, and the like.

Relatively small amounts of the N-acyl ureas are sufficient to make thedetergent composition antiseptic, The amount to be used in a particularinstance will vary over a wide range depending upon such factors as thedegree of effectiveness desired, the particular N-acyl urea employed,and cost. Generally, from 0.2 percent to about 5 percent based on theweight of the detergent will provide desirable antisepsis. It should beunderstood that lesser or greater amounts are operable but withoutsubstantial advantages. A preferred range is an amount in the order offrom about 0.5 percent to about 3 percent, based on the final weight ofthe detergent composition.

In order to more fully describe the nature of the novel compositions ofthe present invention and the manner in which they may be used, thefollowing illustrative specific examples are provided.

EXAMPLE I l-(2,4-Dichlorobenzoyl)-3-(3,4-dichlorophenyl) urea To a 200ml. round bottom flask fitted with a condenser and a drying tube througha Dean-Stark trap, was added 10.0 grams (0.052 mole) of 2,4-dichlorobenzamide in 50 ml. of benzene. The mixture was heated to refluxand any moisture present was removed by azeotropic distillation withbenzene. 3,4- Dichlorophenyl isocyanate 12.0 grams, 0.063 mole) in ml.of o-dichlorobenzene was then added. The temperature was raisedsufficiently to cause the solvent to reflux and benezene was drawn offthrough the Dean- Stark trap. The mixture was then heated under refluxfor a total of 12 hours, and gradually cooled to room temperature. Awhite precipitate was obtained, which was filtered off, air dried andweighed. There was obtained 12 grams (61 percent yield) of l-(2,4-dichlorobenzoyl)-3-(4-dichlorophenyl) urea, (melting point of 222-225C).The reaction product was recrystallized from acetone to give a pure,white crystalline product (melting point 222C.) having the formula:

EXAMPLE 11 Preparation of N-acyl-N-(3,4-dichlorophenyl) ureas In similarprocedure as set forth in Example 1, other EXAMPLE iii Germicidalactivity of the acyl ureas prepared in the above examples was determinedas follows:

acyl ureas were prepared Since 34 dichlomphenyl 5 The various individualacyl ureas were dissolved n isocyanate readily forms 3,3I4,4,tetrachlorocarbani dimethylformamide at l.( percent level. Suspensionsin lide in the presence of water, it is essential that water i E i soapSoluuon prepared T be excluded from the reaction. One method to accom-Soap unhzed was a neutral whne tone} Soap comam plish this is by firstheating the amide in benzene and mg about 20 percent by i f azeotropingany water present. Then, an equimolar l0 and about 80 F by amount, plussome excess, of 3,4-dichlorophenyl isocy- The g a o acy g m soap 9 anatetogether with o-dichlorobenzene solvent are 1,00 g" or P i s? ere S Sadded and the mixture is heated to a higher temperaw comlammg ppm an ppmrespec' ture, at which the benezene is taken off. The mixture nvely t 6my urea is then reacted for about 10 hours under reflux. At the Varymgamounts of the Soap solutlons,comammg the end of this period most of thesolvent is distilled off and acyl ureas were, P P measureid the residueis triturated with benzene or another suitamounts Sterne hqu'd numem soas to Obtam able solvent, filtered, and air dried. In most cases, thisconcentratlons of the acyl urea rangmg from to residue will be found tocontain a small amount of 3,3- PLate S were then allowed to sohdlfy and,4,4-tetrachlorocarbanilide together with the desired 20 streaked aStandard 4 loopful of a 24 hour acyl urea. By boiling the residue inbenzene, filtering Proth cfllture of staphylococcusoaureus FDA whilehot, and cooling the filtrate, the N-acyl urea is mcubaflon for 24 hqursat 37 t bffcterlosttlc precipitated. It may then be separated and airdried. PP was determined" T baFteFIQStatIC endpomt The formation of3,334,41 tetrachlorocarbanilide may hereinafter called the minimuminhibitory concentraalso be avoided by carrying out the reaction in drytolu- 25 reprsentsfihe minimum concentration m R i By this methodequimolar amounts of the bacteriostatic agent necessary to completelyinhibit dichlorophenyl isocyanate and the desired amide reacgrowth Saureus' tam may be added to dry toluene and the reaction Table II givesthe endpoints or the minimum inhibimaintained under reflux. The tolueneis then removed fy concemfallon of the 10 Percent Solutlon, as bydistillation, and the residue is either filtered diwlthout germlcldPadded and wlth the addltlon P the rectly or triturated with petroleumether and then fil- 'N'acyl'N i p y ureas P p tered. The reactionproduct may then be recrystallized amples I and .H: from alcohol orother solvents such as benzene. In order to be sure that the reactionproduct was free TABLE [I of 3,3',4,4-tetrachlorcarbanilide when theproduct was triturated with benzene, the reaction product was Minimumlnhibimry boiled in benzene, filtered while hot, and cooled,Concentration whereupon the acyl urea precipitated and wassepa- R r fi izi if rated and air dried. Where the reaction was run in dry 40 toluene,the product was either recrystallized from al- S g 6 7 cohol or benzene.The acyl ureas obtained are set forth Id Z in Table I. In Table I, thecompounds are listed by set- -gsgu 20 n- 20 ting forth onlythtjRPOl'tlOfl of the general formula. 3 44 20 45 n-C H l05-6 209-n-decenyl 100 5 C1 n-C H 99-100 20 E Z nicotinyl 272-3 20o-chlorophenyl 208 20 R NE NH Cl p-chlorophenyl 273 202,4-dichlorophenyl 0.1-0.5

222 Also, the means by which the removal of 3,3',4,4'-tetgat g t gg gi235-6 fi rachlorocarbanilide is effected is set forth in the table. p

TABLE I Percent Carbon Hydrogen Melting Calcu- Calcu- R polntf 0 Yieldlated Found lated Found Remarks 173 78 45.0 46. 22 3.83 4.05Rocrystallized from alcohol. 15553 51g. 2. Recgstalllzed from benzene.O- 1304 86 51. s 51. 85 5.28 5. 30 Do.

Reegstalllzed from alcohol. 0. 105-6 70 59.0 58.87 7.25 7.01 D0.Q-ii-deceny 100 50 58.1 57. an 6.45 6. 34 Do. n-OiaH27. 99-100 52 60. 860. 76 7. 71 7. 68 DO. Nicotinyl 272-3 04 50. 4 50. 47 2. 00 2. 70Trlturate with acetone. 0-Chlorophenyl... 208 70 40.2 40.51 2. 63 2.05Reerystalllzed from acetone. p-Clilorophenyl 273 87 40. 2 40. 56 2. 632. 00 Trltumte wlth acetone. 2,4-dichlorophonyL. 222 65 44.5 45.02 2.122. 32 Reerystalllzed from acetone.

SA-dichlorophenyl The results obtained above with respect tobacteriostatic activity in the specific soap mentioned above (20/80sodium coco/tallow) are obtained with soaps generally. The activityexhibited by these compounds is independent of the soap vehicle, andother media may be used such as anionic and non-ionic type syntheticdetergents. At the same time, soap is a system in which the compoundsare highly effective. Soap refers to the water-soluble metallic,ammonium, or organic base salts of various fatty acids, such as lard,lauric, oleic, myristic, palmitic, stearic and the like.

While this invention has been described with respect to certainembodiments, it is not so limited; and it is to be understood thatvariations and modifications wherein R is a radical selected from thegroup consisting of aliphatic radicals containing from 2 to 13 carbonatoms and wherein x is selected from the group consisting of chlorine,bromine, fluorine, trichloromethyl and trifluoromethyl; and n is aninteger from 1 to 5.

2. The composition of claim 1 in which said detergent is soap.

3. The composition of claim 1 in which said urea compound is present inan amount from about 0.5 percent to about 3 percent by weight.

4. The composition of claim 1 in which X is chlorine and n is 2.

5. The composition of claim 1 in which X is chlorine, n is 2, and saidhalogenated phenyl is a chlorinated phenyl radical.

6. The composition of claim 5 in which said chlorinated phenyl radicalis 2,4-dichlorophenyl.

7. The composition of claim 5 in which said chlorinated phenyl radicalis 3,4-dichloropheny1.

8. An antiseptic detergent composition comprising a soap and an amountfrom about 0.2 percent to about 5 percent by weight of said detergent,of N-(2,4-

dichlorobenzoyl)-N-3,4-dichlorophenyl urea.

2. The composition of claim 1 in which said detergent is soap.
 3. Thecomposition of claim 1 in which said urea compound is present in anamount from about 0.5 percent to about 3 percent by weight.
 4. Thecomposition of claim 1 in which X is chlorine and n is
 2. 5. Thecomposition of claim 1 in which X is chlorine, n is 2, and saidhalogenated phenyl is a chlorinated phenyl radical.
 6. The compositionof claim 5 in which said chlorinated phenyl radical is2,4-dichlorophenyl.
 7. The composition of claim 5 in which saidchlorinated phenyl radical is 3,4-dichlorophenyl.
 8. An antisepticdetergent composition comprising a soap and an amount from about 0.2percent to about 5 percent by weight of said detergent, ofN-(2,4-dichlorobenzoyl)-N''-3,4-dichlorophenyl urea.